A Short Update on Sugammadex with a Special Focus on Economic

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Review Article Open Access A Short Update on Sugammadex with a Special Focus on Economic Assessment of its Use in North America Cedrick Zaouter1*, Stefano Mion1, Alessandra Palomba2 and Thomas M Hemmerling3 1CHU de Bordeaux, Service d Anesthésie-Réanimation II, F-33000 Bordeaux, France 2University of Pisa, Pisa, Italy 3Department of Anesthesia, Division of Experimental Surgery, McGill University, Montreal, Canada *Corresponding author: Cedrick Zaouter, CHU de Bordeaux, Service d Anesthésie-Réanimation II, F-33000 Bordeaux, France, Tel: +33-5-57-65-68-66; Fax: +33-5-57-65-68-11; E-mail: [email protected] Received date: Jun 06, 2017; Accepted date: Jul 01, 2017; Published date: Jul 04, 2017 Copyright: © 2017 Zaouter C, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Sugammadex offers significant advantages over the current anticholinesterase reversal drugs. Sugammadex used has been approved for the United Stated and for Canada since December 2015 and February 2016, respectively. The present article aims to provide a straightforward and concise review of the most recent literature describing its clinical advantages in routine use. A thorough and cost-effective evaluation has been conducted specifically for North America to determine if its price justifies its inclusion into regular patients’ care. The search examined the relevant literature from January 2013 to October 2016. The present narrative review describes how sugammadex could play a crucial role in the modern conduct of anesthesia. The particular emphasis on sugammadex cost-effective analysis performed in this article suggests that this new reversal agent should be considered for a wider use in North America.

Keywords: Gamma-cyclodextrins; Reversal agent; Delayed examining the literature during the past four years (from January 2013 emergence from anesthesia; Drug-related side effects and adverse to October 2016). The cut-off time for this review was chosen to assess reactions, Anaphylaxis, Cost-benefit analysis and compile the most recent knowledge on the use, advantages, safety and economic viability of sugammadex. Then, the article focused with Introduction particular attention on the economic viability in North America simulating its use and the related cost-effectiveness in concrete clinical Worldwide, neuromuscular blockade (NMB) is reversed mostly with scenarios to determine whether its cost justifies its inclusion into neostigmine, an anticholinesterase drug. However, this association of routine care. medications encompasses several threatening side effects, such as arrhythmias [1] and bronchospasms, when neostigmine outlasts the Objectives of the present review: vagolytic action of the anticholinergic agents [2]. Also, neostigmine has After reading this review, the reader should be able to: noteworthy flaws such as a slow onset of action, as well as the impossibility to reverse deep NMB. In addition, high doses of 1. Prescribe the appropriate dose of sugammadex according to the neostigmine could trigger muscle weakness and consequently depth of NMB and according to the characteristics of particular respiratory complication [3,4]. Sugammadex is a modified cyclic population groups. oligosaccharide that embraces all the characteristics of an ideal NMB 2. Have a thorough understanding of sugammadex intraoperative reversal agent. It is a ring-shaped molecule with hydrophilic properties and postoperative advantages. on its outside allowing it to be water-soluble. The inner side is hydrophobic which attracts amino-steroidal neuromuscular blocking 3. Have a thorough understanding of sugammadex’s safety profile. agents (NMBA) [5]. Rapid plasmatic amino steroidal muscle relaxant 4. Have a critical judgment on the benefit to integrate sugammadex encapsulation creates a concentration gradient that extracts NMBA into clinical practice not only for patients’ safety purposes but also for molecules from the neuromuscular junction to shift back to the economic advantages. plasma. These features result in a significantly faster and safer reversal compared to standard anticholinesterase drugs [6]. Microcalorimetry Which is The Right Dose of Sugammadex According to tests have demonstrated that bonds with rocuronium are preserved for a longer period with a lower dissociation rate than vecuronium [7]. The Depth of The Nmb and How Long Does it Take to Consequently, rocuronium is the most common NMBA administered Fully Reverse Nmb in Comparison to Neostigmine? when sugammadex is used as a reversal agent. From its approval, sugammadex has been used in almost 60 countries, and over 15 Superficial/shallow neuromuscular block (reappearance of million doses have been administered [8]. Since December 2015 and the fourth twitch) February 2016, sugammadex is available in the United-States and Canada, respectively. Thus, the present paper reviews the clinical use of Sugammadex has been shown to be efficient in reversing superficial sugammadex providing readers a short but comprehensive overview. A block defined as a reappearance of 4 twitches after a train-of-four search of the PubMed database was conducted in November 2016, (TOF) with a ratio between the first response and the last one <0.4 [9].

J Anesth Clin Res, an open access journal Volume 8 • Issue 7 • 1000740 ISSN:2155-6148 Citation: Zaouter C, Mion S, Palomba A, Hemmerling TM (2017) A Short Update on Sugammadex with a Special Focus on Economic Assessment of its Use in North America. J Anesth Clin Res 8: 740. doi:10.4172/2155-6148.1000740

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In this clinical situation, 2 mgkg-1 sugammadex are sufficient to obtain NMB with significant time variability (TOF ratio ≥ 0.9 is obtained a TOF ratio ≥ 0.9 in less than 2 min. from 1.8 to 15.2 min) [17]. At present, we recommend 4 mgkg-1 sugammadex to reverse deep NMB in order to obtain a TOF ratio ≥ 0.9 Moderate neuromuscular blockade (TOF count 1 to 3) within 2 min.

Sugammadex is also effective in reversing quickly moderate NMB Profound neuromuscular blockade (can’t intubate, can’t defined as a TOF count of 2 [10]. In 98 patients recruited in a multicenter randomized trial with moderate levels of NMB, Blobner et ventilate scenario) al. [11] found that the mean length of time necessary to obtain a TOF Sugammadex is also effective for urgent reversal in emergency ratio of 0.9 with 2.0 mgkg-1 sugammadex was 1.5 min, whereas 18.6 situations such as ‘can’t intubate, can’t ventilate’ even when a high-dose min were required with 50 µgkg-1 of neostigmine. Blobner and of rocuronium is administered. Chambers et al. [18] performed a collaborators have also shown that predictability of response was systematic review and found three randomized clinical trials that greater with sugammadex than neostigmine, with 98% of sugammadex compared 16 mg.kg-1 sugammadex with placebo or succinylcholine. In patients versus only 11% of neostigmine patients recovering to a TOF these trials, sugammadex was administered 3 or 5 min after 1 or 1.2 ratio of 0.9 within 5 min [11]. Interestingly, the efficacy to reverse mgkg-1 rocuronium, respectively. Chambers et al. [18] concluded that moderate NMB does not differ whether anesthesia is maintained with after a profound NMB, recovery of neuromuscular transmission after halogenated agents or with propofol [12]. Sugammadex has also been sugammadex was markedly faster than after placebo or than shown to reverse efficiently rocuronium moderate NMB in both spontaneous recovery from succinylcholine. Lee et al. [19] are the only Caucasian and Chinese subjects [13]. ones to compare the time to recover to a TOF ratio ≥ 0.9 between the -1 -1 Therefore, we recommend 2 mgkg-1 sugammadex to reverse administration of 1 mgkg succinylcholine and 16 mgkg sugammadex administered 3 min after an intubating dose of 1.2 moderately deep NMB (1 to 3 twitches present) in order to obtain a -1 TOF ratio ≥ 0.9 within 2 min. mgkg rocuronium. Time to recovery was significantly faster for the association rocuronium-sugammadex compared with succinylcholine with 4.4 ± 0.7 vs. 7.1 ± 1.6 min, respectively. In the rocuronium- Deep neuromuscular blockade (Post-Tetanic Count=1-2) sugammadex group, 87% of the patients reached a TOF ratio of 0.9 in One of the most compelling factors of sugammadex is its ability to less than 3 min, which was shorter than in the succinylcholine group reverse - reliably and quickly - deep NMB defined as 0 twitches after a by 4 to 5 min. Although sugammadex has been shown to be rapid and TOF stimulation or 1 to 2 twitches after a tetanic stimulation, Post- efficient to reverse rocuronium-induced profound NMB, it has been Tetanic Count=1-2 (PTC=1-2) [9,10]. Recently, Rahe-Meyer et al. [14] reported that it could require up to 17 min to fully reverse a profound enrolled patients from 10 different institutions in Germany. At the end block [20]. The reason is probably related to the wide range of of the surgery, 140 patients with a PTC=1-2 received randomly 4.0 individual responses and receptor affinity to a single dose of mgkg-1 sugammadex or placebo. Spontaneous recovery from deep rocuronium [21]. Nevertheless, it seems that there is an agreement that rocuronium-induced NMB is on average 40 times slower than rapid sequence induction (RSI) performed with the rocuronium- sugammadex. Four mgkg-1 sugammadex reversed deep NMB rapidly sugammadex association could bring some advantages [22,23]. The and consistently (2 min, interquartile 1.6-2.8 min). When neostigmine combination is compelling especially because it does not induce is used to reverse deep NMB, a mean of 50.4 min is necessary to reach fasciculations, which increase oxygen consumption during apnea [24]. a TOF ratio of 0.9 [9]. Doses of sugammadex below 1 mg.kg-1 have It also allows regaining spontaneous ventilation on average 3 min been shown to be initially effective to reverse rocuronium-induced earlier compared to succinylcholine [25]. Table 1 summarizes the deep NMB, but lead to the gradual reappearance of the NMB in both dosage of sugammadex according to the neuromuscular blockade adults [15] and children [16]. In contrast, sugammadex doses ranging depth and the relative time necessary to fully reverse it. from 1 to 2 mg.kg-1 have shown to reverse rocuronium-induced deep

Immediate rescue reversal Deep NBM Moderate NMB Superficial NMB Sugammadex PTC=0 TOF=0 PTC=1-2 TOF count=1-3 TOF ratio

Dose 16 mgkg-1 [40] 4 mgkg-1 [10] 2- 4 mgkg-1 [10,16] 2 mgkg-1 [16]

Time to reach a TOF ratio ≥ 0.9 4.4 min [40] 3.3-1.5 min [10] 2.3-1.5 min [10,16] 1,5 min [16]

Abbreviation: NMB: Neuromuscular Blockade; ENT: Ear Nose and Throat

Table 1: The dosage of sugammadex according to the neuromuscular blockade depth and the relative time necessary to fully reverse it.

Considerations for Specific Population Groups difference is that the onset time seems faster but the recovery time is similar to the adult population [27]. Sugammadex is not recommended Pediatric in infants below 2 years of age [10]. According to a recent review, 2 mgkg-1 of sugammadex seems to be a safe dosage to reverse moderate NMB for this population [26]. A

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Pregnant and breastfeeding women Best surgical conditions performing deep Laparoscopic surgery, Only one recent multicenter randomized controlled trial enrolling neuromuscular blockade bariatric surgery Madsen [35,36] 240 patients undergoing a C-section has been published showing the non-inferiority of 1 mgkg-1 rocuronium for rapid-sequence induction orthopedic fracture -1 repositioning, dislocation compared with 1 mgkg succinylcholine. In the rocuronium group, Deep NMB until the end of reduction, laparotomy, and sugammadex was given to reverse NMB. No difference in the Apgar the surgery mucosectomy Dubois et al. [37] score between the two groups was noticed. Less resistance during laryngoscopy and a lower incidence of postoperative myalgia were Patients with diminished respiratory reserve (i.e. found in the group receiving rocuronium and sugammadex [28]. Since patients with obstructive there is only little oral absorption, sugammadex can be administrated lung disease, sleep apnoea safely in breastfeeding women [10]. The rocuronium-sugammadex Faster reversal than and neuromuscular combination has been claimed to be an advantage in parturients with neostigmine disease) Schaller et al. [10] neurologic disease [29]. Sugammadex is now part of the UK Obstetric Abbreviation: NMB, Neuromuscular Blockade; ENT, Ear Nose and Throat Anaesthetist Association’s newest algorithm for management after failed tracheal intubation as rocuronium can be fully reversed by Table 2: Intraoperative advantages using sugammadex as reversal sugammadex within 3 min instead of 9 min to reach spontaneous agent. recovery using succinylcholine [30]. Advantages of sugammadex during the postoperative period Obese patients Although anesthesiologists believe that postoperative residual It is generally recommended to administer sugammadex according paralysis induced by non-depolarizing NMBA occurs in less than 1% to the body weight [31]. In contrast, Loupec et al. [32] advocate that in of the cases [39], residual curarization is a very frequent complication morbidly obese patients, 4 mgkg-1 sugammadex using ideal body that could involve up to 83% of the patients in the postoperative period weight provides satisfactory reversal of deep rocuronium-induced even with the introduction of shorter-acting muscle relaxants [40]. NMB. To support this statement, they conducted a randomized Residual blockade can trigger adverse postoperative pulmonary events, controlled trial in 50 morbidly obese patients. They found that reversal pharyngeal dysfunction, the need for urgent tracheal reintubation and of deep NMB occurred within 10 min in 93% (255 ± 62 sec) and in prolonged stay in post-anesthesia care unit (PACU) [41]. Reversal with 77% (429 ± 102 sec) of the patients when they received 4 mgkg-1 or 2 sugammadex appears to be associated with significantly less mgkg-1 of sugammadex based on the ideal body weight, respectively. postoperative pulmonary complications, especially in the elderly Objections have been raised because dosage according to the body population [42]. Also, sugammadex seems to be associated with a weight could reverse NMB more rapidly, [33] but Loupec et al. claimed shorter length of stay in PACU, because of a faster diaphragmatic that longer recovery time was not clinically significant [32]. Other recovery, less pain [43] and fewer episodes of PONV. Table 3 authors advocate that for morbidly obese patients, the total summarizes the postoperative advantages using sugammadex as a sugammadex dose could be safely reduced to the ideal body weight reversal agent. (IBW) + 40% [34]. Postoperative Elderly patients advantages Evidence References The time required to reach a TOF ratio of 0.9 is longer in patients Reduced pulmonary older than 69 years [27]. However, this difference is not clinically Less perioperative complications in elderly respiratory adverse events ASA 3/4 patients Ledowski et al. [42] significant and does not justify different dose recommendations [10]. Less PONV Ledowski et al. [42]

Advantages of Sugammadex Use During Daily Practice Less pain Castro et al. [43]

Advantages of sugammadex when a deep NMB is performed Abbreviation: PONV, Postoperive Nausea and Vomiting; ASA, American Society of Anesthesiologist physical status. Maintenance of deep NMB appears to offer better postoperative pain relief and optimal surgical conditions during laparoscopic Table 3: Postoperative advantages using sugammadex as reversal agent. surgeries [35,36], orthopedic fracture repositioning, dislocation reduction, laparotomy, and mucosectomy [37]. However, anesthesiologists are still worried to use deep levels of NMB until the Advantages of Sugammadex in Patients with end of the surgery because of the impossibility to reverse reliably and Comorbidities satisfactorily such a deep NMB [38]. Deep NMB maintained by rocuronium until the end of the surgery, and reversed with Patients with muscular or neuromuscular disease sugammadex seems to be a combination that increases the quality of Patients with muscular and neuromuscular diseases could be certain operational conditions, especially in obese patients. Table 2 challenging for the anesthesiologists who need to perform an summarizes the intraoperative advantages of deep NMB. endotracheal intubation to offer the best surgical conditions. The Intraoperative challenge is caused by the extreme sensitivity of this population to advantages Type of surgery / Patients References NMBAs, which could lead to an overlong period of mechanical ventilation that could trigger respiratory and cardiovascular

Page 4 of 10 complications and also result in death [44]. Therefore, the combination mgkg-1 rocuronium at the induction and deep NMB during surgery rocuronium-sugammadex seems to be a safe and reliable option for presented an episode of recurarization 3 h after injection of 6 mgkg-1 patients with myasthenia gravis, multiple sclerosis, dermatomyositis, sugammadex and attainment of a TOF ratio of 0.9 before extubation Sjogren’s syndrome, Becker muscular dystrophy, Duchene muscular [58]. Bellod et al. described a similar case of delayed recurarization in a dystrophy, myotonic dystrophy, spinal muscular atrophy, Strumpell- patient with known chronic renal failure 2 h after arrival in the PACU, Lorrain disease, and amyotrophic lateral sclerosis [10,42,45-50]. The despite that the appropriate dose of sugammadex was injected at the rocuronium-sugammadex combination has been studied mainly in end of surgery [59]. Bellod and colleagues managed this event patients with myasthenia gravis. De Boer et al. [51] have published the successfully by administrating a second dose of sugammadex in the largest case series (n=21) of patients with myasthenia gravis presenting PACU. Postoperative neuromuscular monitoring to detect potentially an Osserman class II (n=13) or class III (n=8) receiving steroidal delayed recurarization should be implemented in patients with renal muscle relaxants followed by sugammadex. At the end of surgery, 2 or failure throughout a prolonged postoperative period. The 4 mg kg-1 sugammadex were administered to reverse moderate or deep sugammadex-rocuronium compound has been shown to be dialyzable NMB, respectively. Time to recover to a TOF ratio ≥ 0.9, was 80 sec. with a reduction of 70 % of its plasma concentration after the first (range 30 to 268) and 165 sec. (range 105 to 240) for moderate and session and reduced by 50% after the following sessions [22,60]. Of deep NMB, respectively. In their case series, no patient had residual particular interest for patients with severe renal failure requiring a RSI, postoperative muscle paralysis and all were discharged from the PACU is the significantly lower increase in potassium concentration when the to the surgical ward without problem. Their results were similar to 20 combination rocuronium-sugammadex is injected compared to other case reports describing patients with myasthenia gravis receiving succinylcholine [61]. the appropriate amount of sugammadex to reverse muscle paralysis found upon completion of the surgery. Only one case report described Advantages of sugammadex in case of rocuronium- that RSI using high-dose of rocuronium followed by an adequate dose induced anaphylactic shock of sugammadex in a myasthenic patient is possible and should be a strategy to bear in mind for this type of population in the emergency Anaphylaxis is a rare but life-threatening complication. Its incidence setting [52]. In contrast, Kiss et al. [53] were the first to describe the in anesthesia is estimated to range from 1 in 10000 to 1 in 20000 cases inefficacy of a high dose of sugammadex (12 mgkg-1) to reverse [62]. In anesthesia, the drugs inducing more frequently an promptly and efficiently NMB in a myasthenic patient with an anaphylactic reaction are the NMBA with the following incidence: Osserman score of III with a pre-endotracheal intubation TOF ratio of succinylcholine (61%), atracurium (19.5%), cisatracurium (6%), 0.97 receiving 30 mg of rocuronium. Unfortunately, the authors did vecuronium (4.5%), rocuronium (4%), pancuronium (3%), and not present the reason for the delay in recovery and no postoperative mivacurium (2%) [63]. The incidence of anaphylaxis induced by complications were presented. sugammadex is significantly lower than those related to NMBA injection [64]. Via its peculiar action, sugammadex has been suggested Patients with liver dysfunction as a novel treatment therapy to inhibit mast cells and basophils activation triggering anaphylaxis. This hypothesis was confirmed by Sugammadex seems to be safe and well tolerated in patients with evidence from several case reports describing hemodynamic and liver dysfunction undergoing hepatic surgery as demonstrated by respiratory restoration few minutes after sugammadex administration Fujita et al. [54]. They administered a bolus of rocuronium followed by [62]. However, a recent case report described the inefficacy of low a continuous infusion in 31 patients. In their observational study, no doses of sugammadex to reverse rocuronium-induced anaphylaxis patients showed evidence of residual paralysis postoperatively and no [65]. Lately, Raft et al. [66] reported that even high doses of adverse event related to the use of sugammadex was reported. One case sugammadex (14 mgkg-1) could be ineffective to reverse a report also described its safe use in a patient with acute porphyria [55]. rocuronium-induced anaphylaxis. Platt et al. [67] support the The reason why it is safe to use it in this population is probably related inefficacy of sugammadex to reverse rocuronium-induced anaphylaxis to the sugammadex-rocuronium compound excretion occurring publishing the first case-control study on this topic describing 13 mainly via urine, thus not interacting with the liver function [7]. patients with a presumed rocuronium-induced anaphylaxis who received a sugammadex injection. They concluded that sugammadex Patients with renal failure does not interfere with the correction of the immune disorder caused The kidney excretes sugammadex rapidly and unchanged. Thus, its by rocuronium but could improve the hemodynamic parameters by clearance could be delayed in patients with severe kidney failure. A increasing the muscle tone thus increasing cardiac preload [67]. Platt’s prospective study has shown that 4 mgkg-1 sugammadex could be used trial encompasses a substantial methodological flaw because there was to reverse rocuronium-induced deep NMB in patients with severe no case to use as control [68]. Thus, further studies on that matter renal failure (creatinine clearance <30 mlmin-1) without residual should be conducted to draw final conclusions looking specifically at postoperative NMB [56]. Nevertheless, clinicians should bear in mind the timing of sugammadex administration, which has been suggested that a substantial variability in the times to reach a TOF ratio of 0.9 in to be a crucial element to gain clinical benefit [69]. In a case of an these patients with chronic renal failure might be observed [56]. Such anaphylaxis reaction, conventional treatment using epinephrine and variability could be explained by the kidney donor status [57]. When fluid loading must be the first line treatment and sugammadex as a the transplanted kidney comes from a recently deceased donor the second line might be envisioned. renal function does not recover instantly [57]. However, considering the limited number of trials and patients with severe renal impairment exposed to prolonged sugammadex-rocuronium complex, caution should be maintained in this population. A recent case report describing a patient with severe renal impairment who received 1.2

Page 5 of 10 Essential Knowledge to Use Sugammadex Safely affect serotonin type 3 receptors (such as ondansetron), ranitidine and verapamil [60]. Metabolism Adverse Effects Sugammadex and the rocuronium/sugammadex complex are water- soluble and are quickly excreted via urine [5]. The elimination half-life of sugammadex is on average 2 h in adult anesthetized patients with Hypersensitivity and Anaphylaxis normal renal function. Because of its unique architecture, it has a low Anaphylaxis is a life-threating complication. In more than 58% of penetration of the blood–brain barrier and a low placenta transfer [7]. the time, the causal agent is a NMBA [81]. However, allergic anaphylaxis to sugammadex is a rare event [64]. Nonetheless, Interactions hypersensitivity is the main reason why the American Food and Drug Association raised concern and delayed approval of sugammadex [82]. Sugammadex possesses a positively charged quaternary nitrogen In 2014, Tsur et al. [64] screened all previously reported cases on chain, which allows a strong and unique affinity for rocuronium. In sugammadex anaphylactic reactions. They found a total of 15 probable contrast, both endogenous and exogenous steroidal molecules have a cases of anaphylaxis to sugammadex. Anaphylaxis occurred within 5 negligible affinity to sugammadex, because they do not have a three- min of sugammadex administration. None of these 15 patients who dimensional profile that permits strong bonds with this quaternary developed an allergic reaction to sugammadex died [64]. The reason nitrogen chain. Consequently, affinity for cortisone, hydrocortisone, why patients can develop hypersensitivity to sugammadex without and aldosterone is 120-fold weaker than the one for rocuronium. previous exposure is still unknown. Tsur and colleagues hypothesized a Furthermore, affinity for atropine, verapamil, and ketamine is 400 to sensitization of cyclodextrins found in foods and cosmetics [64]. To 700-fold lower than for rocuronium [7]. Zwiers et al. [70] analyzed the obtain the FDA approval, the company selling sugammadex sponsored probability of the most common drugs used along with sugammadex a hypersensitivity trial in awake volunteers in 2014 [82]. Three to displace it. Among all the molecules studied, toremifene, fusidic hundred seventy-five individuals received an intravenous bolus of acid, and flucloxacillin are the only molecules noticed to displace saline, 4 mg.kg-1 sugammadex or 16 mgkg-1 sugammadex. One subject rocuronium from sugammadex. Theoretically, these molecules could met the criteria for anaphylaxis after an injection of 16 mgkg-1 generate a delay in reaching a TOF ratio of ≥ 0.9. Nonetheless, a RCT sugammadex. In 2014, the same company published post-marketing including 24 patients did not encounter residual postoperative muscle data concerning 11.5 million sugammadex exposures. From these relaxation with concomitant prescription of diclofenac or flucloxacillin exposures, they retrieved 273 reports of anaphylaxis with 237 of 241 [71]. Gulec et al. [72] have recently conducted a randomized trial in 60 patients improving with conventional. By the end of 2015, after children undergoing adenotonsillectomy receiving saline or -1 additional site inspections and sensitivity investigations, the FDA dexamethasone 0,5 mgkg after induction. At the end of surgery, approved sugammadex [82]. In summary, the rate of anaphylactic anesthesia was terminated, and when 2 twitches of the TOF -1 reaction is low, and an episode can be managed with standard therapy reappeared, all patients were given 2 mgkg sugammadex. There was most of the time [69,83]. no significant difference between groups neither in the time to recover a TOF ratio of 0.9 nor in the time to meet the extubation criteria [72]. Dexamethasone seems to decrease the effectiveness of sugammadex to Longer clotting time and increased bleeding reverse rocuronium-induced NMB in a dose-dependent fashion [42]. In a randomized, placebo-controlled, three-period cross-over trial, Hence, high-dose of dexamethasone used concomitantly with De Kam et al. [84] described a dose-related transient prolongation of sugammadex should be done with caution until further research can the prothrombin time and the partial thromboplastin time in 8 healthy provide more evidence. Antibiotics are known to potentiate NMB and subjects. The same authors conducted a randomized, double-blind, consequently limiting the effect of the traditional anticholinesterase placebo-controlled, four-period cross-over study and found that when reversal agent. Hudson et al. [73] have conducted a study to determine healthy subjects received either unfractionated heparin or low- whether antibiotics could reduce sugammadex’s ability to reverse molecular-weight heparin, both moderate (4 mgkg-1) and high (16 steroidal muscle relaxant agents. Analyzing data from 197 patients mgkg-1) doses of sugammadex did not clinically affect partial from 19 different sites, they found that antibiotics known to interfere thromboplastin time nor anti-Xa activity [85]. In a prospective with acetylcholine release (kanamycin, gentamicin, vancomycin, investigation, Raft et al. [86] looked at the effects of sugammadex clindamycin and bacitracin) did not disturb the capacity of administration on routine coagulation tests and bleeding. Their sugammadex (4 mgkg-1) to reverse NMB induced by rocuronium. findings do not support that 2 or 4 mgkg-1 sugammadex is associated Magnesium is also a factor known to inhibit neuromuscular with a longer clotting time. Another double-blinded randomized study transmission [74]. However, it seems that pre-treatment with enrolling patients undergoing orthopedic surgery confirms that magnesium does not alter the efficacy of the recommended dose of sugammadex does not increase the bleeding risk [87]. sugammadex after moderate and deep blockade with rocuronium [75-78]. A recent case report described the successful reversal of QTc prolongation rocuronium using sugammadex in a patient with pre-eclampsia who received magnesium intraoperatively [79]. Finally, sugammadex may Transient prolongation of the QT interval (>500 ms) following the interact with hormonal contraceptive drugs via unwanted binding, administration of sugammadex has been described in patients potentially reducing their clinical efficacy. Thus, female patients should anesthetized with sevoflurane or propofol [88,89]. However, several be informed of the reduced efficacy of hormonal contraceptives if they large studies proved that sugammadex does not seem to trigger receive a dose of sugammadex [80]. Finally, to avoid precipitation, significant QT/QTc prolongation [90], even with extremely high doses sugammadex should not be injected concomitantly with drugs that of sugammadex (32 mgkg-1) [91]. Sugammadex does not seem to produce effects on cholinesterase, nicotinic or muscarinic receptors,

Page 6 of 10 consequently minimizing the risk of cardiovascular side effects. To the calculated - conservatively - the expense considering that each OR contrary, the association neostigmine-atropine is known to have minute costs 10 $Can (or 30 $US). The price of sugammadex was significant cardiovascular effects and is clearly associated with calculated on the assumption that a patient has a weight of 75 kg. The significant QTc prolongation [90]. cheapest combination of vials was used, and any unused drug in a vial was considered wasted. A vial with the smallest dose of sugammadex Respiratory adverse events contains 200 mg and corresponds to approximately 100 $Can and 100 $US. Reversing rocuronium-induced NMB with sugammadex, we Negative pressure pulmonary edema is a rare complication that could hypothesize that the cost per case corresponds to: occurs after general anesthesia, especially after extubation in the elderly population. Suzuki et al. experienced a case of negative pressure y=z - k - x pulmonary edema after tracheal extubation following reversal of y=cost of a case using sugammadex rocuronium using sugammadex. They have attributed residual muscular blockade on the upper airway muscle associated with large z=sugammadex cost per case inspiratory forces created by the faster respiratory muscles recovery k=time saved per case after sugammadex injection [92]. Basaranoglu et al. [93] described an episode of respiratory distress caused by a rapid increase in chest wall x=operation staff value per minute rigidity after sugammadex decurarization. They attributed this event to opioid-induced chest rigidity. McGuire and Dalton reported an ‘Value of each minute of OR time saved’ – evaluation unexpected finding in 9 consecutive patients. They observed A) In patients with superficial blockade (reappearance of the fourth laryngospasms occurring two minutes after the administration of twitch): Sugammadex could reduce the mean time to reach a TOF ratio sugammadex. The laryngospasm was spontaneously reversible, and no of 0.9 by 17 min [9]. Patients with shallow NMB need 2 mg.kg-1 casualties were reported [94]. Nevertheless, the clinical relevance of sugammadex to reverse rocuronium-induced blockade, which, on these findings should be elucidated with further trials. average, corresponds to 150 mg. The dose is obtained using 1 vial. Is Sugammadex Cost-effective? y=100 $Can-17 min x 10 $Can, y’=100 $US-17 min x 30 $US y=100 $Can-170 $Can, y’=100 $US-510 $US, Economic impact of sugammadex y=-70 $Can, y’=-410 $US Although no large-scale randomized study has been conducted to In this case the OR time saved will lower the cost related to surgery determine sugammadex’s economic impact, recent literature gathers by 70 $Can and 410 $US in Canada and in the United States, more and more clues that sugammadex might actually be cost effective. respectively. According to Chamber’s [18] and Paton’s [95] economic analysis, sugammadex cost-effectiveness relies on two concepts. The first B) In patients with moderate NMB (TOF count=1-3): Randomized concept is that faster recovery time can be achieved using sugammadex controlled trials comparing rocuronium and sugammadex with compared to neostigmine. The second concept is that time saving rocuronium and neostigmine suggested that sugammadex reduces the could be converted into valuable activities. Rapid NMB reversal can mean time to reach a TOF ratio of 0.9 by 18.6 min [11]. Patients with lower the operating room (OR) occupancy with the consequential moderate NMB should be given 2-4 mg.kg-1 sugammadex to reverse potential to increase the OR workflow especially for short cases rocuronium-induced blockade, which, on average, corresponds to 225 [96,97]. Also, by eliminating postoperative residual curarization and mg. The last dose is obtained with 2 vials (200 $Can and 200 $US). related pulmonary complications, sugammadex might reduce the costs y=200 $Can-18.6 min x 10 $Can, y’=200 $US-18.6 min x 30 $US related to the time necessary to discharge the patients from the PACU, which would result in a more rapid turnover between surgeries y=200 $Can-186 $Can, y’=200 $US-558 $US [42,98-101]. y=14 $Can, y’=-358 $US Economic evaluation in real clinical scenario In this case the OR time saved will not lower the cost related to the surgery but increase it by 14 $Can. On the contrary, in the United Our hypothesis to sustain the favorable cost-effectiveness of States, it might save up to 358 $US. sugammadex relies on the conversion of the time saved via a rapid NMB reversal with less postoperative complication into extra-surgical C) In patients with deep NMB (PTC=1-2): Patients with deep NMB time to perform more surgical interventions. Thus, we performed an require 4 mg.kg-1 sugammadex to reverse rocuronium-induced economic assessment analyzing: blockade, which corresponds to 300 mg. The dose is obtained with 2 vials. Sugammadex reduces the mean time to obtain a TOF ratio ≥ 0.9 1. The ‘value of each minute of OR time saved’ by 47.5 min in this clinical condition (50.4 min reversing with 2. The ‘value of each minute of PACU time saved’ neostigmine–2.9 min reversing with sugammadex) [9]. 3. The ‘value of each minute of length of hospital stay saved’ y=200 $Can- 47.5 min x 10 $Can, y’=200 $Can-47.5 min x 30 $US We based our analysis on the most recent operating time cost y=200 $Can-475 $Can, y’=200 $US-1425 $US evaluation in Canada and United States. In Canada, the cost has been y=-275 $Can, y’=1225 $US estimated, on a per-minute basis, to range from 10 to 40 $Can [102]. In the United States, it has been previously estimated to be of 2000 $US In this case, the OR time saved will lower the cost related to the per hour (30 $US per minute) [103]. In our economic evaluation, we surgery by 275 $Can and by 1225 $US in Canada and in the United States, respectively.

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D) Clinical case scenarios: 1) Case scenario 1: An Budget adenotonsillectomy takes on average 40 min when performed under Budget balance per moderate NMB and reversed with sugammadex [106]. We could Number of balance per OR day in Clinical Case additional cases OR day in United States assume that if NMB is reversed with neostigmine the total length of scenarios performed per day Canada ($Can) ($US) the procedure will take an additional 17 min (to completely reverse the blockade to a 0.9 TOF ratio) [9]. Considering an 8 h OR schedule (480 Short surgery with min) and assuming 20 min of turnover between two moderate NMB 2 -28 716 adenotonsillectomies, 8 cases could be performed using sugammadex Long surgery with (480 min/(40 min for surgery+20 min for turnover)=8). In contrast, moderate NMB 1 -14 358 only 6.2 cases could be performed using neostigmine (Total OR working hour/adenotonsillectomy conducted using neostigmine=480/ Short surgery with deep NMB 2 550 2450 (40+17+20)=6.2). Thereby, sugammadex could be considered cost- effective in short surgeries with moderate NMB (i.e. Abbreviation: NMB: Neuromuscular Blockade; $Can: Canadian dollars; $US: adenotonsillectomy) because it provides extra-surgical time to perform United States dollars. almost two more cases per day. In the United States, it could be assumed that sugammadex could also lower the daily OR cost by 716 Table 4: Outline of the value of each min of OR time saved using $US (358×2). suagammadex. 2) Case scenario 2: A bariatric laparoscopic procedure in obese patients with a BMI ≥ 40 kg.m-2 takes on average 90 min when Evaluation of both the ‘value of each minute of PACU’ and performed under moderate NMB and reversed with sugammadex [97]. the ‘value of each minute of hospital length of stay time Supposing 30 min of turnover between two procedures in an 8 h OR saved’ schedule (480 min), 4 cases could be performed (total OR working hour/ bariatric laparoscopic procedure under moderate NMB reversed Such estimation was difficult to perform because data in the using sugammadex+min for turnover=480/90+30=4). Only 3.3 cases literature is insufficient to determine the impact of the type of reversal could be carried out per day reversing the NMB with neostigmine. agent on postoperative pulmonary complications (i.e. incidence of atelectasis, pneumonia, pulmonary edema) with the related increased Time to perform a bariatric laparoscopic procedure under moderate cost (i.e. antibiotic therapy and the extended length of hospital stay). In NMB reversed with neostigmine was calculated as such: [bariatric addition, quantitative neuromuscular monitoring is underused in laparoscopic procedure performed under moderate NMB+min for North America [105]. Thus, the association between postoperative turnover=(115+30)=145 min. Total OR working hour/ bariatric neuromuscular recovery and the presence of residual NMB leading to laparoscopic reversed using neostigmine + min for turnover =480/ postoperative complication is difficult to verify and inferences are hard (115+30)=480/145=3.3]. to establish. However, two assumptions could be formulated. First, it Again, even for this clinical case scenario, sugammadex could be could be expected that sugammadex brings potential favorable considered cost-effective because it offers extra-surgical time to economic repercussion within the elderly population that is prone to perform at least one more case per day, lowering the operational cost develop postoperative pulmonary complications [99]. The latter by 358 $US. consideration is of paramount importance bearing in mind that the elderly population will drastically increase in the near future [106]. 3) Case scenario 3: A laparoscopic hysterectomy takes on average 70 Second, it could be assumed that administrating sugammadex min when performed under deep NMB and reversed with routinely would force anesthesiologists to monitor the muscle sugammadex [104]. In an 8 h OR schedule (480 min) and assuming 30 relaxation depth. Hence, it could be claimed that using sugammadex, min of turnover between two laparoscopic hysterectomies, 4.8 cases the incidence of postoperative residual curarization may lower along could be performed using sugammadex (total OR working hour/ with the related pulmonary complications that increase patients’ laparoscopic hysterectomy performed under deep NMB reversed using hospital length of stay [97]. sugammadex + min for turnover=480/70+30=4.8). In contrast, only 3.25 cases could be carried out using neostigmine. Time to perform a Our economic evaluation for North America shows that laparoscopic hysterectomy using neostigmine was calculated as such: sugammadex appears to be cost-effective. It seems that it allows (laparoscopic hysterectomy performed under deep NMB and reversed performing a higher number of different surgical interventions with sugammadex–time to reverse the blockade with sugammadex) accomplished under both moderate and deep NMB. It also appears +time to reverse with neostigmine a deep NMB+min for that sugammadex lowers the daily OR cost for surgeries requiring deep turnover=(70–2.9)+50.4=117.5 min. Total or working h/laparoscopic NMB in both Canada and United States. In the United States, hysterectomy performed using neostigmine+min for turnover=480/ sugammadex could also lower the OR cost for surgeries requiring (117.5+30)=480/147.5=3.25. Hence, sugammadex can be considered moderate NMB. Several european cost-effectiveness investigations are cost-effective for laparoscopic procedures performed under deep NMB in-line with our estimation [95-97]. A recent Canadian investigation (i.e. laparoscopic hysterectomy) because it could lower both the also confirmed our analysis using a discrete event simulation model surgical cost (by 275 $Can or 1225 $US for each case) and provide specifically developed to explore the effect of sugammadex versus extra-surgical time to perform 1.55 (4.8-3.25) more cases per day. neostigmine on the OR efficiency and postoperative patients’ outcome. Table 4 summarizes the evaluation of the value of each minute of OR The authors that have conducted this research advocate that using time saved using suagammadex. sugammadex to reverse moderate NMB is likely to lower the incidence of residual NMB. When it is administrated to reverse deep NMB, sugammadex is likely to increase the OR efficiency and lower the rate of postoperative residual curarization. Our analysis has several

Page 8 of 10 limitations; it does not take into consideration the rate of both surgery 10. Schaller SJ, Fink H (2013) Sugammadex as a reversal agent for cancellation and emergency intervention. Also, the calculation of the neuromuscular block: an evidence-based review. Core Evid 8: 57-67. OR time cost was based on an investigation conducted in a teaching 11. Blobner M, Eriksson LI, Scholz J, Motsch J, Della Rocca G, et al. (2010) hospital. The length of the procedure encompassing teaching time Reversal of rocuronium-induced neuromuscular blockade with could be longer in comparison with a non-teaching hospital. Therefore, sugammadex compared with neostigmine during sevoflurane anaesthesia: results of a randomised, controlled trial. Eur J Anaesthesiol; the estimation may be underestimated for a non-teaching hospital. 27: 874-881. Another limit is that reports regarding the cost-effectiveness of 12. Vanacker BF, Vermeyen KM, Struys MMRF, Rietbergen H, sugammadex on both the ‘value of each minute of PACU’ and ‘length Vandermeersch E, et al. (2007) Reversal of rocuronium-induced of hospital stay’ saved are scarce and may depend on institutional neuromuscular block with the novel drug sugammadex is equally habits due to the large differences in staff practice and logistics from effective under maintenance anesthesia with propofol or sevoflurane. one center to another. Finally, there is a lack of prospective large Anesth Analg 104: 563-568. sample size conducted in North America on this topic. 13. Wu X, Oerding H, Liu J, Vanacker B, Yao S, et al. (2014) Rocuronium blockade reversal with sugammadex vs. neostigmine: randomized study Conclusions in Chinese and Caucasian subjects. BMC Anesthesiol 14: 53. 14. Rahe-Meyer N, Berger C, Wittmann M, Solomon C, Abels E, et al. (2015) Although more expensive than the traditional reversal agents, Recovery from prolonged deep rocuronium-induced neuromuscular sugammadex shows exceptional and unique features. It is more blockade: A randomized comparison of sugammadex reversal with predictable and allows much faster recovery than neostigmine for both spontaneous recovery. Anaesthesist 64: 506-512. superficial and moderate NMB. In addition, sugammadex can reverse 15. Eleveld DJ, Kuizenga K, Proost JH, Wierda JMKH (2007) A temporary decrease in twitch response during reversal of rocuronium-induced deep NMB while neostigmine is not efficient. The sugammadex-related muscle relaxation with a small dose of sugammadex. Anesth Analg 104: incidence of adverse events is very low; it can be used safely to reverse 582-584. rocuronium in patients with neuromuscular disease, liver dysfunction 16. Iwasaki H, Takahoko K, Otomo S, Sasakawa T, Kunisawa T, et al. (2014) A or renal failure. 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J Anesth Clin Res, an open access journal Volume 8 • Issue 7 • 1000740 ISSN:2155-6148